Muscle regeneration compositions and uses therefor

Abstract

The present invention relates to a method of treating and/or ameliorating one or more symptoms of sarcopenia and age-related muscle degeneration in a mammal.

1 . A method of preventing or treating sarcopenia in a mammal, said method comprising at least the step of administering to a mammal in need thereof, an amount of at least a first myostatin antagonist effective to treat said sarcopenia in said mammal. 
     
     
         2 . The method of  claim 1 , wherein said at least a first myostatin antagonist is selected from the group consisting of:
 (a) an anti-myostatin antibody;   (b) a myostatin peptide immunogen, myostatin multimer or myostatin immuno-conjugate capable of eliciting an immune response and blocking myostatin activity;   (c) a protein inhibitor of myostatin selected from a truncated Activin type II receptor, a myostatin pro-domain and follistatin, or a functional fragment of said protein inhibitor;   (d) a myostatin inhibitor released into culture from cells overexpressing myostatin;   (e) a dominant negative of myostatin selected from the Piedmontese allele and mature myostatin peptides having a C-terminal truncation at a position at or between amino acid positions 300 to 375;   (f) a small peptide comprising the amino acid sequence WMCPP and which is capable of binding to and inhibiting myostatin;   (g) a splice-variant of myostatin;   (h) a regulator of the myostatin pathway; and   (i) an antisense polynucleotide, RNAi, siRNA or an anti-myostatin ribozyme capable of inhibiting myostatin activity by inhibiting myostatin gene expression.   
     
     
         3 . The method of  claim 2 , wherein said at least a first myostatin antagonist is a dominant negative of myostatin selected from the group consisting of a Piedmontese allele and mature myostatin peptides having a C-terminal truncation at a position of from between about amino acid position 300 and amino acid position 375. 
     
     
         4 . The method of  claim 3 , wherein said at least a first myostatin antagonist is a mature myostatin peptide having a C-terminal truncation at amino acid position 300, 310, 320, 330, 335 or 350. 
     
     
         5 . The method of  claim 2 , where said at least a first myostatin antagonist is a splice variant of a myostatin polypeptide that has at least about 70% sequence identity to a polypeptide comprising a sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14. 
     
     
         6 . The method of  claim 5 , wherein said at least a first myostatin antagonist is a splice variant of a myostatin polypeptide that comprises a sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14. 
     
     
         7 . The method of  claim 2 , wherein said at least a first myostatin antagonist is a regulator of the myostatin pathway, and further where said antagonist is a polypeptide that comprises an amino acid sequence that is at least 70% identical to the amino acid sequence of the “mighty” peptide disclosed in SEQ ID NO: 16 or SEQ ID NO: 18. 
     
     
         8 . The method of  claim 7 , wherein said at least a first myostatin antagonist is a regulator of the myostatin pathway, and further wherein said antagonist is a polypeptide that comprises the amino acid sequence of SEQ ID NO: 16 or SEQ ID NO: 18. 
     
     
         9 . The method of  claim 1 , wherein said mammal is a human. 
     
     
         10 . A method for increasing the activation of satellite cells in a mammal, said method comprising at least the step of administering to a mammal in need thereof, an amount of at least a first myostatin antagonist as defined in  claim 2 , effective to increase the activation of satellite cells in said mammal. 
     
     
         11 . The method of  claim 10 , wherein said mammal is a human that has, is suspected of having, or has been diagnosed with, at least one age-related muscle disorder. 
     
     
         12 . The method of  claim 11 , wherein said at least one age-related muscle disorder is sarcopenla. 
     
     
         13 . A method for increasing the migration of myoblasts in a regenerating mammalian muscle tissue, said method comprising at least the step of providing to said tissue, an amount of at least a first myostatin antagonist as defined in  claim 2 , effective to increase the migration of said myoblasts in said regenerating mammalian muscle tissue. 
     
     
         14 . The method of  claim 13 , wherein said mammal is a human that has, is suspected of having, or has been diagnosed with, at least one age-related muscle disorder. 
     
     
         15 . The method of  claim 14 , wherein said at least one age-related muscle disorder is sarcopenia. 
     
     
         16 . A method for increasing the migration of macrophages in a regenerating mammalian muscle tissue, said method comprising at least the step of providing to said tissue, an amount of at least a first myostatin antagonist as defined in  claim 2 , effective to increase the migration of said myoblasts in said regenerating mammalian muscle tissue. 
     
     
         17 . The method of  claim 16 , wherein said mammal is a human that has, is suspected of having, or has been diagnosed with, at least one age-related muscle disorder. 
     
     
         18 . The method of  claim 17 , wherein said at least one age-related muscle disorder is sarcopenia. 
     
     
         19 . The method of  claim 1 , wherein the at least a first myostatin antagonist is formulated for oral, intravenous, cutaneous, subcutaneous, intradermal, nasal, pulmonary, intramuscular or intraperitoneal administration. 
     
     
         20 . The method of  claim 1 , further comprising the additional step of administering to said mammal at least a second myostatin antagonist. 
     
     
         21 . The method of  claim 20 , wherein said at least a second myostatin antagonist is selected from the group consisting of:
 (a) an anti-myostatin antibody;   (b) a myostatin peptide immunogen, myostatin multimer or myostatin immuno-conjugate capable of eliciting an immune response. and blocking myostatin activity;   (c) a protein inhibitor of myostatin selected from a truncated Activin type II receptor, a myostatin pro-domain and follistatin, or a functional fragment of said protein inhibitor;   (d) a myostatin inhibitor released into culture from cells overexpressing myostatin;   (e) a dominant negative of myostatin selected from the Piedmontese allele and mature myostatin peptides having a C-terminal truncation at a position at or between amino acid positions 300 to 375;   (f) a small peptide comprising the amino acid sequence WMCPP and